Project Summary/Abstract j . Prescription opioids (mu opioid receptor agonists) are the drugs of choice for treating moderate to severe pain, despite well-documented adverse effects of those drugs (e.g., abuse, respiratory depression) and significant public health concerns. Mu opioids are the most widely abused of all prescription medications and fatal overdoses have reached epidemic levels. Thus, there is a dire need for more effective treatments for pain with fewer deleterious effects. Kappa opioid receptor agonists do not produce respiratory depression and are not likely to be abused; however, clinical use of kappa opioids has been precluded by adverse effects in humans, such as dysphoria, hallucinations, and diuresis. If these centrally mediated adverse effects can be avoided, then kappa opioids might be promising targets for treating pain and would be preferred to mu opioids that have a high risk of abuse and overdose. Our laboratory showed that by combining a kappa opioid with a non-opioid drug that also produces antinociception (e.g., a cannabinoid receptor agonist), smaller doses of each drug in a the mixture produce antinociceptive effects in an additive manner. If adverse effects are not apparent at smaller doses, then kappa opioids in combination with cannabinoids could have therapeutic potential for treating pain. The therapeutic potential of kappa opioid/cannabinoid mixtures is perhaps greatest for treating chronic inflammatory pain over other types of pain. The proposed studies will test the hypothesis that a kappa opioid/cannabinoid mixture further enhances antinociceptive but not adverse effects in rats with chronic inflammation due to increased function at kappa and cannabinoid receptors that mediate antinociception peripherally and spinally. Aim 1 characterizes the antinociceptive effects of a kappa opioid/cannabinoid mixture to test the hypothesis that smaller doses of drugs in a mixture have antinociceptive effects that are greater than additive. Aim 2 uses operant choice procedures to quantify adverse effects of a kappa opioid/cannabinoid mixture to test the hypothesis that the potency of a mixture is decreased in rats with inflammation. Aim 3 compares kappa opioid and cannabinoid receptor function from rats with and without inflammation. These studies explore a novel and innovative approach (kappa opioid/cannabinoid mixture) for treating pain without the risk of abuse that currently limits the clinical use of mu opioids. Additionally, this grant will support a postdoctoral training plan for the applicant to develop a unique research trajectory and transition to a career as an independent investigator.